Interferon In Systemic Lupus Erythematosus Research Articles

Evaluation of RNase therapy in systemic lupus erythematosus: a randomised phase 2a clinical trial of RSLV-132

BackgroundCirculating, extracellular RNA is the primary trigger of type I interferon in systemic lupus erythematosus (SLE), and interferon is known to play a central pathogenic role in the disease. RSLV-132...

The XIST lncRNA is a sex-specific reservoir of TLR7 ligands in SLE.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a dramatic sex bias, affecting 9 times more women than men. Activation of Toll-like receptor 7 (TLR7) by self-RNA is a central pathogenic process leading to aberrant production of type I interferon (IFN) in SLE, but the specific RNA molecules that serve as TLR7 ligands have not been defined. By leveraging gene expression data and the known sequence specificity of TLR7, we identified the female-specific X-inactive specific transcript (XIST) long noncoding RNA as a uniquely rich source of TLR7 ligands in SLE. XIST RNA stimulated IFN-α production by plasmacytoid DCs in a TLR7-dependent manner, and deletion of XIST diminished the ability of whole cellular RNA to activate TLR7. XIST levels were elevated in blood leukocytes from women with SLE compared with controls, correlated positively with disease activity and the IFN signature, and were enriched in extracellular vesicles released from dying cells in vitro. Importantly, XIST was not IFN inducible, suggesting that XIST is a driver, rather than a consequence, of IFN in SLE. Overall, our work elucidated a role for XIST RNA as a female sex-specific danger signal underlying the sex bias in SLE.

Type I Interferons in Systemic Lupus Erythematosus: A Journey from Bench to Bedside.

Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type I IFN signature and SLE disease activity have yielded conflicting results. In addition to type I IFNs, type II and III IFNs may overlap and also contribute to the IFN signature. Different genetic backgrounds lead to overproduction of type I IFNs in SLE and contribute to the breakdown of peripheral tolerance by activation of antigen-presenting myeloid dendritic cells, thus triggering the expansion and differentiation of autoreactive lymphocytes. The consequence of the continuous stimulation of the immune system is manifested in different organ systems typical of SLE (e.g., mucocutaneous and cardiovascular involvement). After the discovery of the type I IFN signature, a number of different strategies have been developed to downregulate the IFN system in SLE patients, finally leading to the successful trial of anifrolumab, the second biologic to be approved for the treatment of SLE in 10 years. In this review, we will discuss the bench to bedside translation of the type I IFN pathway and put forward some issues that remain unresolved when selecting SLE patients for treatment with biologics targeting type I IFNs.

Interferon Lambda Regulates Cellular and Humoral Immunity in Pristane-Induced Lupus

A pivotal role of type I interferons in systemic lupus erythematosus (SLE) is widely accepted. Type III interferons (IFN-λ) however, the most recently discovered cytokines grouped within the interferon family, have not been extensively studied in lupus disease models yet. Growing evidence suggests a role for IFN-λ in regulating both innate and adaptive immune responses, and increased serum concentrations have been described in multiple autoimmune diseases including SLE. Using the pristane-induced lupus model, we found that mice with defective IFN-λ receptors (Ifnlr1−/−) showed increased survival rates, decreased lipogranuloma formation and reduced anti-dsDNA autoantibody titers in the early phase of autoimmunity development compared to pristane-treated wild-type mice. Moreover, Ifnlr1−/− mice treated with pristane had reduced numbers of inflammatory mononuclear phagocytes and cNK cells in their kidneys, resembling untreated control mice. Systemically, circulating B cells and monocytes (CD115+Ly6C+) were reduced in pristane-treated Ifnlr1−/− mice. The present study supports a significant role for type III interferons in the pathogenesis of pristane-induced murine autoimmunity as well as in systemic and renal inflammation. Although the absence of type III interferon receptors does not completely prevent the development of autoantibodies, type III interferon signaling accelerates the development of autoimmunity and promotes a pro-inflammatory environment in autoimmune-prone hosts.

Recommendations for the use of COVID-19 vaccines in patients with immune-mediated kidney diseases.

Coronavirus Disease 19 (COVID-19) vaccine platforms are becoming available and are the most promising strategy to curb the spread of SARS-CoV-2 infections. However, numerous uncertainties exist regarding the pros and cons of vaccination, especially in patients with (immune-mediated) kidney diseases on immunosuppressive drugs. Here, members of the Immunonephrology Working Group (IWG) of the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) discuss thirteen frequently-asked questions regarding safety and efficacy of the most promising vaccine candidates. Post-marketing surveillance should be performed to estimate the rate of vaccine response (humoral and cellular) of different vaccine platforms, and surveillance of disease activity following administration of COVID-19 vaccines. Some of the candidates induce signaling pathways which also promote autoimmune kidney diseases, e.g. type I interferons in systemic lupus erythematosus. Efficacy estimates would thus far favor the use of selected COVID-19 vaccines, such as BNT162b2, mRNA-1273 or Gam-COVID-Vac. Humoral immune response after vaccination should be monitored using appropriate assays. Even in the absence of neutralizing antibodies patients might be protected by a sufficient cellular immune response capable to reduce severity of COVID-19. A reduced vaccine response after the use of CD20-depleting agents is anticipated, and it is particularly important to discuss strategies to improve vaccine response with these patients. Distancing and shielding measures remain important as not all vaccines fully protect from coronavirus infection. In-depth information about the most pressing vaccine questions is essential to reduce vaccine hesitancy of patients.

Analysis of Trans-Ancestral SLE Risk Loci Identifies Unique Biologic Networks and Drug Targets in African and European Ancestries

Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of African ancestry (AA) experience the disease more severely and with an increased co-morbidity burden compared to European ancestry (EA) populations. We hypothesize that the disparities in disease prevalence, activity, and response to standard medications between AA and EA populations is partially conferred by genomic influences on biological pathways. To address this, we applied a comprehensive approach to identify all genes predicted from SNP-associated risk loci detected with the Immunochip. By combining genes predicted via eQTL analysis, as well as those predicted from base-pair changes in intergenic enhancer sites, coding-region variants, and SNP-gene proximity, we were able to identify 1,731 potential ancestry-specific and trans-ancestry genetic drivers of SLE. Gene associations were linked to upstream and downstream regulators using connectivity mapping, and predicted biological pathways were mined for candidate drug targets. Examination of trans-ancestral pathways reflect the well-defined role for interferons in SLE and revealed pathways associated with tissue repair and remodeling. EA-dominant genetic drivers were more often associated with innate immune and myeloid cell function pathways, whereas AA-dominant pathways mirror clinical findings in AA subjects, suggesting disease progression is driven by aberrant B cell activity accompanied by ER stress and metabolic dysfunction. Finally, potential ancestry-specific and non-specific drug candidates were identified. The integration of all SLE SNP-predicted genes into functional pathways revealed critical molecular pathways representative of each population, underscoring the influence of ancestry on disease mechanism and also providing key insight for therapeutic selection.

Biologics targeting type I interferons in SLE: A meta-analysis and systematic review of randomised controlled trials.

The feed-forward loop of type I interferons (IFNs) production and subsequent immunopathology of systemic lupus erythematosus (SLE) has been hypothesised to be disrupted with inhibition of IFNα or type I IFN receptor subunit 1 (IFNAR). This systematic review and meta-analysis present the treatment efficacy and safety profile of monoclonal antibodies inhibiting IFNα or IFNAR. A search was done using Medline, Embase and ClinicalTrials.gov for biologics targeting IFNα or IFNAR in SLE up to 3 Jan 2020. For the meta-analysis, analyses of binary variables were pooled using odds ratio (OR) with the Mantel Haenszel model. Anifrolumab 300 mg (n = 3 studies, 927 patients) was more effective than placebo in achieving SRI(4) (pooled OR = 1.91, CI 1.11-3.28, P = 0.02) and BICLA response (pooled OR = 2.25, CI 1.72-2.95, P < 0.00001). In SLE patients with high type I IFN gene signature, SRI(4) response was not achieved with anifrolumab in 2 studies, 450 patients. Treatment with IFNα and IFNAR inhibitors (n = 7 studies, 1590 patients) increased the risk of herpes zoster infection (pooled OR = 3.72, CI 1.88-7.39, P = 0.0002), upper respiratory tract infections, nasopharyngitis and bronchitis. This meta-analysis substantiates IFNAR as a therapeutic target in SLE. Inhibition of type I IFNs predisposes to herpes zoster and other viral infections.

The regulation and pharmacological modulation of immune complex induced type III IFN production by plasmacytoid dendritic cells

ObjectivePatients with systemic lupus erythematosus (SLE) have an ongoing interferon (IFN) production due to an activation of plasmacytoid dendritic cells (pDCs), which can be triggered to type I IFN synthesis by RNA containing immune complexes (RNA-IC). Considering emerging data suggesting a role of type III IFN in the SLE disease process, we asked if RNA-IC can induce type III IFN production in pDC and how this production can be regulated.MethodsPeripheral blood mononuclear cells (PBMCs) or immune cell subsets were isolated from healthy blood donors or SLE patients and stimulated with IC containing U1 snRNP and SLE-IgG (RNA-IC). Hydroxychloroquine (HCQ) and an interleukin receptor 1-associated kinase 4 inhibitor (IRAK4i) were added to cell cultures. Cytokine mRNA levels were determined with a microarray and protein levels with immunoassays. Single-cell RNA sequencing of pDCs using ddSEQ technology was performed.ResultsType III IFN mRNA and protein was induced in RNA-IC-stimulated pDC-NK and pDC-B cell co-cultures. A subset of activated pDCs (3%) expressed both type III and type I IFN mRNA. IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6, or granulocyte-macrophage colony-stimulating factor (GM-CSF) enhanced IFN-λ1/3 production 2–5-fold. HCQ and an IRAK4i blocked the RNA-IC-triggered IFN-λ1/3 production (p < 0.01). IFN-α2b and GM-CSF increased the proportion of SLE patients producing IFN-λ1/3 in response to RNA-IC from 11 to 33%.ConclusionsType III IFN production is triggered by RNA-IC in pDCs in a TLR-MyD88-dependent manner, enhanced by NK and B cells as well as several pro-inflammatory cytokines. These results support a contributing role for both type I and type III IFNs in SLE, which needs to be considered when targeting the IFN system in this disease.

Gene expression analysis delineates the potential roles of multiple interferons in systemic lupus erythematosus

A role for interferon (IFN) in systemic lupus erythematosus (SLE) pathogenesis is inferred from the prominent IFN gene signature (IGS), but the major IFN species and its relationship to disease activity are unknown. A bioinformatic approach employing individual IFN species gene signatures to interrogate SLE microarray datasets demonstrates a putative role for numerous IFN species, with prominent expression of IFNB1 and IFNW signatures. In contrast with other SLE-affected organs, the IGS is less prominent in lupus nephritis. SLE patients with active and inactive disease have readily detectable IGS and the IGS changes synchronously with a monocyte signature but not disease activity, and is significantly related to monocyte transcripts. Monocyte over-expression of three times as many IGS transcripts as T and B cells and IGS retention in monocytes, but not T and B cells from inactive SLE patients contribute to the lack of correlation between the IGS and SLE disease activity.

Novel genetic associations with interferon in systemic lupus erythematosus identified by replication and fine-mapping of trait-stratified genome-wide screen

Background/PurposeHigh serum interferon alpha (IFN-α) is an important heritable phenotype in systemic lupus erythematosus (SLE) which is involved in primary disease pathogenesis. High vs. low levels of IFN-α are associated with disease severity and account for some of the biological heterogeneity between SLE patients. The aim of the study was to replicate and fine-map previously detected genetic associations with serum IFN-α in SLE. MethodsWe previously undertook a case-case genome-wide association study of SLE patients stratified by ancestry and extremes of phenotype in serum IFN-α. Single nucleotide polymorphisms (SNPs) in seven loci identified in this screen were selected for follow up in a large independent cohort of 1370 SLE patients (703 European-ancestry, 432 African ancestry, and 235 Amerindian ancestry). Each ancestral background was analyzed separately, and ancestry-informative markers were used to control for ancestry and admixture. ResultsWe find a rare haplotype spanning the promoter region of EFNA5 that is strongly associated with serum IFN-α in both African-American and European-American SLE patients (OR = 3.0, p = 3.7 × 10−6). We also find SNPs in the PPM1H, PTPRM, and NRGN regions associated with IFN-α levels in European-American, Amerindian, and African-American SLE patients respectively. Many of these associations are within regulatory regions of the gene, suggesting an impact on transcription. ConclusionThis study demonstrates the power of molecular sub-phenotypes to reveal genetic factors involved in complex autoimmune disease. The distinct associations observed in different ancestral backgrounds emphasize the heterogeneity of molecular pathogenesis in SLE.

A potential association between IL-3 and type I and III interferons in systemic lupus erythematosus.

ObjectivesPlasmacytoid dendritic cells (pDCs), through the production of type 1 interferons (IFNs) and other cytokines, are major contributors to systemic lupus erythematosus (SLE) pathogenesis. IL‐3 promotes pDC survival, but its role in SLE is not well characterised. This study investigated serum IL‐3 and IFN levels, and a whole blood ‘IL‐3 gene signature’, in human SLE.MethodsSerum cytokine levels were measured by ELISA in n = 42 SLE patients, and n = 44 healthy donors. IL‐3‐regulated genes were determined by RNASeq of healthy donor whole blood cells (WBCs) stimulated in vitro with IL‐3 for 6 or 24 h. Whole blood cell RNASeq analysis was undertaken in a separate cohort of n = 31 SLE patients, and n = 28 healthy donors.ResultsSerum IL‐3 levels correlated with IFNα (r = 0.612, 95% CI 0.455–0.733, P < 0.001) and type III IFN (r = 0.585, 95% CI 0.406–0.720, P < 0.0001). IL‐3 stimulation of WBC in vitro altered 794 genes (−1 ≥ logFC ≥ 1, FDR < 0.05), of which 35 overlapped with genes differentially expressed between SLE and healthy donors. These 35 genes were expressed in 27/31 SLE donors, revealing the presence of an ‘IL‐3 gene signature’. There was strong correlation between the IL‐3 signature and an IFN signature, as determined by hierarchical clustering of the 500 most variable genes in SLE donors (r = 0.939, 95% CI 0.898–0.964, P < 0.0001).ConclusionA dual IL‐3/IFN gene signature is a feature of SLE. An association between IL‐3 and IFN raises the possibility that dual blockade of IL‐3 and IFN may be especially useful for SLE patients with this dual cytokine gene signature.

Type I and II interferons commit to abnormal expression of chemokine receptor on B cells in patients with systemic lupus erythematosus

Memory B cells are increased in systemic lupus erythematosus (SLE) cases, but the qualitative abnormalities and induction mechanism of these cells are unclear. Here, we subclassified B cells by their chemokine receptor expression and investigated their induction mechanism. The peripheral blood of patients with SLE showed higher levels of CXCR5− and CXCR3+ B cells. CXCR5−CXCR3+ B cell levels were elevated in patients with active SLE, which decreased with improving disease conditions. Interferon (IFN)-γ stimulation increased CXCR3 expression, whereas IFN-β stimulation reduced CXCR5 expression in B cells. Furthermore, CXCR5−CXCR3+ B cells were induced by a combination of IFN-β and IFN-γ stimulation. Renal tissue examination of patients with active lupus nephritis confirmed the presence of CD19+CXCR3+ B cells. Collectively, the results revealed qualitative abnormalities accompanying reduced CXCR5 expression via type I IFN and enhanced CXCR3 expression via type II IFN in SLE, suggesting their involvement in B cell infiltration into tissues and inflammatory pathogenesis.

Single cell analysis revealed distinct B-cell subpopulations that produce or respond to type I interferon in SLE

Abstract We previously showed that B-cell endogenous expression of interferon beta (IFNβ) is associated with the development of autoreactive B cells in BXD2 autoimmune mice. As among all type I IFNs, IFNβ exhibits the highest affinity to IFNAR1 and IFNAR2 and IFNβ also can stimulate IFNαs, there is a pressing need for a better understanding of the source and responses of IFNβ in systemic lupus erythematosus (SLE). Flow cytometry and super-resolution imaging analysis showed increased expression of IFNβ in B cells obtained from PBMCs of SLE patients compared to healthy controls. The importance of SLE B-cell endogenous IFNβ in regulating TLR7-mediated responses was identified when CL264 (a TLR7 ligand) plus anti-Ig-induced CD69 and survival of purified B cells were significantly and equivalently suppressed by an anti-IFNβ or an anti-IFNAR1 blocking antibody. We next carried out single cell qRT-PCR analysis to determine if B-cell endogenous IFNβ acts in an autocrine or paracrine manner to modulate IFN stimulated genes (ISGs). Hierarchical analysis revealed three prominent and consistent clusters, consisting of an IFNB+ cluster, an ISG+ cluster, and an IFNA+ cluster in naïve B cells isolated from 3 SLE patients. Cells within the IFNB+ cluster expressed higher levels of IFNB, IFNA1, IFNA8, and TLR7. Cells within the ISG+ cluster expressed higher levels of IFNAR1, IFNAR2, BAFFR, MX1, RIG1 and TLR9. Cells within the IFNA+ cluster expressed higher levels of IFNA4, IFNA10, IFNA14, IFNA16, IFNA17, and TLR3. Together, the results reveal (1) B cells as an important source of IFNβ in modulating TLR7 responses in SLE; (2) a well-orchestrated program in modulating IFNβ donor versus responder B cells; and (3) some patients may benefit from specific targeting of IFNβ.

Recent developments in systemic lupus erythematosus pathogenesis and applications for therapy.

Systemic lupus erythematosus (SLE) pathogenesis is complex. Aberrancies of immune function that previously were described but not well understood are now becoming better characterized, in part through recognition of monogenic cases of lupus-like disease. We highlight here recent descriptions of metabolic dysfunction, cytokine dysregulation, signaling defects, and DNA damage pathways in SLE. Specifically, we review the effects of signaling abnormalities in mammalian target of rapamycin, Rho kinase, Bruton's tyrosine kinase, and Ras pathways. The importance of DNA damage sensing and repair pathways, and their influence on the overproduction of type I interferon in SLE are also reviewed. Recent findings in SLE pathogenesis expand on previous understandings of broad immune dysfunction. These findings have clinical applications, as the dysregulated pathways described here can be targeted by existing and preclinical therapies.

An update on the role of type I interferons in systemic lupus erythematosus and Sjögren's syndrome.

Systemic lupus erythematosus (SLE) and primary Sjögren's syndrome (pSS) share several clinical and laboratory features, including an overexpression of type I interferon (IFN) regulated genes. The genetic background to this IFN signature and the role of the type I IFN system in the disease process have been partly clarified. Here, we summarize the latest information concerning the type I IFN system in both diseases. A number of gene variants in the type I IFN signalling pathways associate with an increased risk for both SLE and pSS in several ethnicities. The function of some risk gene variants has been elucidated, as well as the importance of epigenetic changes in type I IFN regulated genes. MicroRNA-451 and miR-302d have been shown to target IFN regulatory factor 8 and 9, suggesting that noncoding RNAs can control the IFN system. A prominent type I IFN activation is related to several disease manifestations, and in SLE to a more severe disease phenotype. Phase II studies in SLE suggest beneficial effects of blocking the type I IFN receptor. The activated type I IFN system in SLE and pSS has a strong genetic component, is important in the disease etiopathogenesis and can be targeted.

Dendritic cells and interferons in systemic lupus erythematosus

Abstract Systemic lupus erythematosus (SLE) is an autoimmune disorder with a genetic basis, and is characterized by the appearance of autoantibodies, the formation and deposition of circulating immune complexes, and chronic inflammation in various organs. It is of multifactorial origin, and in genetically predisposed individuals, environmental factors and hormonal components play a key role in the immune system of the disease. About 25 genetic loci have been identified, indicating the importance in this pathology. However, the concordance rate for SLE is only 25% among monozygotic twins. An example of this is the deficiencies of the initial components in the classical serum complement pathway such as C1q, C2 or C4, which, although rare, confer genetic susceptibility for SLE at a rate of 30% in the case of C4 deficiency, and more than 90% for C1q deficiency. It was also demonstrated that C1q inhibits plasmacytoid dendritic cells (pDCs) in the secretion of interferon-alpha (IFN-α), thus providing a new link between complement deficiency and activation of the IFN pathway. Therefore, IFN-α is considered to have a central role in the pathogenesis of SLE, with high serum concentrations being found in outbreaks of this disease. These IFN exert prominent immunoregulatory effects, suggesting that this cytokine is key, not only in the innate immune system, but also in adaptive immune responses. Taking these facts into account, it can be anticipated that pDCs, the main source of IFN secretion, are involved in this autoimmune disease. In this review, we will focus on the participation of and IFNs in SLE.

Role of interferons in SLE.

Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that affects many different organ systems, with excessive production of type I interferons (IFNs) and autoantibodies against nucleic acids as hallmarks. Activation of the type I IFN system in SLE is due to continuous stimulation of plasmacytoid dendritic cells by endogenous nucleic acids, leading to sustained type I IFN production. This is reflected by an overexpression of type I IFN-regulated genes or an IFN signature. Type I IFNs have effects on both the innate and adaptive immune systems, which contribute to both loss of tolerance and the autoimmune disease process. In this review, we discuss the current understanding of IFNs in SLE, focusing on their regulation, the influence of genetic background, and environmental factors and therapies that are under development aiming to inhibit the type I IFN system in SLE.

Distinct Functions of Autoantibodies Against Interferon in Systemic Lupus Erythematosus: A Comprehensive Analysis of Anticytokine Autoantibodies in Common Rheumatic Diseases.

Anticytokine autoantibodies occur across a range of hematologic, pulmonary, and infectious diseases. However, systematic investigation of their presence and significance in autoimmune diseases is lacking. This study was undertaken to examine the distinct functions of anticytokine autoantibodies in patients with systemic lupus erythematosus (SLE) compared to patients with other rheumatic diseases and healthy controls. Serum samples from patients with SLE (n = 199), patients with primary Sjögren's syndrome (SS) (n = 150), patients with rheumatoid arthritis (RA) (n = 149), and healthy controls (n = 200) were screened for 24 anticytokine autoantibodies using a multiplex bead-based assay. To evaluate the biologic activity of anticytokine autoantibodies, their ability to block cytokine-induced signal transduction or protein expression was measured. RNA sequencing was performed on whole blood in a subset of healthy controls and patients with SLE. Patients with SLE and those with SS had a striking excess of autoantibodies against interferons and the interferon-responsive chemokine interferon-inducible protein 10 (IP-10). Only autoantibodies against type I interferon, interleukin-12 (IL-12), and IL-22 exhibited neutralizing activity. In SLE, the presence of anti-interferon-γ autoantibodies was correlated with more severe disease activity, higher levels of anti-double-stranded DNA antibodies, and elevated expression of interferon-α/β-inducible genes. Conversely, in SLE patients with blocking anti-interferon-α autoantibodies, the type I interferon gene expression signature was normalized. Anti-type III interferon autoantibodies (λ2, λ3) and anti-IP-10 autoantibodies were newly recognized in SLE patient serum, and autoantibodies against macrophage-colony stimulating factor, IL-4, IL-7, IL-17, and IL-22, none of which have been previously identified in rheumatic conditions, were discovered. Anticytokine autoantibodies are associated with distinct patterns of disease in SLE, SS, and RA. Anti-interferon autoantibodies are overrepresented in patients with SLE and those with SS, and fall into distinct functional classes, with only a subset of anti-type I interferon antibodies exhibiting neutralizing activity. Anti-interferon-γ autoantibodies are correlated with increased disease activity and interferon-related gene expression, suggesting that such autoantibodies may contribute to the pathogenesis of SLE.

Targeting type I interferon in systemic lupus erythematosus

Type I interferon (IFN) is an attractive therapeutic target in systemic lupus erythematosus (SLE), a notion bolstered by the positive results of a recent clinical trial of the anti-IFN antibody sifalimumab in patients with SLE. Interestingly, sifalimumab worked best in patients with high expression of IFN-induced genes, supporting the idea that subgroups of patients might be targeted specifically.

Targeted therapeutics in SLE: emerging strategies to modulate the interferon pathway.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by impaired immune tolerance, resulting in the generation of pathogenic autoantibodies and immune complexes. Although autoreactive B lymphocytes have been the first targets for biologic therapies in SLE, the importance of the innate immune system, and in particular, pathways involved in interferon (IFN) signaling, has emerged. There are now data supporting a central role for a plasmacytoid dendritic cell-derived type I IFN pathway in SLE, with a number of biologic therapeutics and small-molecule inhibitors undergoing clinical trials. Monoclonal antibodies targeting IFN-α have completed phase II clinical trials, and an antibody against the type I IFN receptor is entering a phase III trial. However, other IFNs, such as IFN gamma, and the more recently discovered type III IFNs, are also emerging as targets in SLE; and blockade of upstream components of the IFN signaling pathway may enable inhibition of more than one IFN subtype. In this review, we discuss the current understanding of IFNs in SLE, focusing on emerging therapies.